EP2536733B1 - Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation - Google Patents

Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation Download PDF

Info

Publication number
EP2536733B1
EP2536733B1 EP20110704227 EP11704227A EP2536733B1 EP 2536733 B1 EP2536733 B1 EP 2536733B1 EP 20110704227 EP20110704227 EP 20110704227 EP 11704227 A EP11704227 A EP 11704227A EP 2536733 B1 EP2536733 B1 EP 2536733B1
Authority
EP
European Patent Office
Prior art keywords
spiro
furo
dimethyl
isopropyl
pyran
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP20110704227
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2536733A1 (en
Inventor
Holger Wagner
Daniela Berta
Klaus Fuchs
Riccardo Giovannini
Dieter Wolfgang Hamprecht
Ingo Konetzki
Ruediger Streicher
Thomas Trieselmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP20110704227 priority Critical patent/EP2536733B1/en
Publication of EP2536733A1 publication Critical patent/EP2536733A1/en
Application granted granted Critical
Publication of EP2536733B1 publication Critical patent/EP2536733B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to 1,3,6,7,8,9-hexahydro-furo[3,4-c]quinoline derivatives having the following chemical scaffold which is structurally defined by the formula I
  • the invention further relates to pharmaceutical compositions containing one or more compounds according to the invention as well as the use of the compounds according to the invention as medicaments, particularly for preparing pharmaceutical compositions for the treatment and/or prevention of cardiometabolic or cardiovascular disorders.
  • the invention relates to processes for preparing the compounds and pharmaceutical compositions according to the invention.
  • the invention relates to compounds and pharmaceutical compositions according to the invention for use in methods of inhibiting CETP as well as of treating and/or preventing cardiovascular or related disorders.
  • CETP cholesterol ester transfer protein
  • the aim of the present invention is to find new compounds particularly those which have valuable pharmacological properties, especially those which are active with regard to the enzyme CETP, such as e.g. 1,3,6,7,8,9-hexahydro-furo[3,4-c]quinoline derivatives.
  • a further aim of the present invention is to discover 1,3,6,7,8,9-hexahydro-furo[3,4-c]quinoline derivatives which have an inhibitory effect on the enzyme CETP in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.
  • a further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of cardiometabolic or cardiovascular disorders, particularly hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia and atherosclerosis.
  • cardiometabolic or cardiovascular disorders particularly hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia and atherosclerosis.
  • the present invention relates to compounds which are structurally defined by the formula I wherein
  • the compounds of formula I according to the invention and the pharmaceutically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the enzyme cholesteryl ester transfer protein (CETP).
  • CETP cholesteryl ester transfer protein
  • the present invention also relates to the pharmaceutically acceptable salts of the compounds of formula I according to the invention with inorganic or organic acids.
  • This invention also relates to pharmaceutical compositions, comprising at least one compound of formula I according to the invention or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.
  • compositions comprising or made of (e.g. by combining or mixing of) at least one compound according to the invention (including a pharmaceutically acceptable salt thereof), and one or more excipients, carriers and/or diluents.
  • This invention also relates to the use of at least one compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition which is suitable for the treatment and/or prevention of diseases, disorders or conditions which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), such as e.g. those cardiometabolic or cardiovascular disorders mentioned herein.
  • CETP cholesteryl ester transfer protein
  • This invention also relates to the use of at least one compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition which is suitable for the treatment and/or prevention of cardiovascular and related disorders, such as e.g. hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia or atherosclerosis.
  • cardiovascular and related disorders such as e.g. hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia or atherosclerosis.
  • This invention also relates to the use of at least one compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for inhibiting the enzyme cholesteryl ester transfer protein (CETP).
  • CETP cholesteryl ester transfer protein
  • This invention also relates to a compound according to the present invention which is suitable for use in therapy and/or prophylaxis, e.g. for the treatment and/or prevention of diseases or conditions which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), e.g. cardiovascular, cardiometabolic and related disorders, such as e.g. any of those diseases, disorders and conditions mentioned herein.
  • CETP cholesteryl ester transfer protein
  • This invention also relates to a compound according to the present invention which is suitable for inhibiting the enzyme cholesteryl ester transfer protein (CETP).
  • CETP cholesteryl ester transfer protein
  • the invention further relates to a process for preparing a pharmaceutical composition according to the invention, comprising incorporating a compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof in one or more inert carriers and/or diluents preferably by a non-chemical method.
  • the present invention also relates to a pharmaceutical compound or composition according to this invention for use in a method of treating and/or preventing a condition which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), e.g. a cardiovascular, cardiometabolic or related disorder, such as e.g. any of those diseases and conditions mentioned herein, said method comprising administration of said compound or composition, optionally alone or in combination (such as e.g. separately, sequentially, simultaneously, concurrently or chronologically staggered) with one or more other therapeutic agents, such as e.g. selected from those mentioned herein.
  • CETP cholesteryl ester transfer protein
  • the present invention also relates to a compound of formula I according to this invention or a pharmaceutically acceptable salt thereof for use in a method of treating and/or preventing a cardiovascular, cardiometabolic or related disorder selected from atherosclerosis, dyslipidemia (e.g. mixed dyslipidemia), hyperbeta-lipoproteinemia, hypoalpha-lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypolipoproteinemia, hyperlipoproteinemia, hypo-HDL cholesterolemia, hyper-LDL cholesterolemia, familial hypercholesterolemia, peripheral vascular disease, hypertension, endothelial dysfunction, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, arteriosclerosis, coronary heart disease, coronary artery disease, coronary vascular disease or congestive heart failure, vascular complications of diabetes, insulin resistance, obesity, metabolic syndrome, diabetes (especially type 2 diabetes meliitus) or endotoxemia, said method comprising administration
  • a HMG-CoA reductase inhibitor e.g. a statin
  • the present invention also relates to a compound of formula I according to this invention or a pharmaceutically acceptable salt thereof for use in a method of increasing patient's levels of HDL cholesterol and/or decreasing patient's levels of VLDL cholesterol and/or of LDL cholesterol, optionally in combination with one or more other therapeutic agents, such as e.g. selected from those mentioned herein, such as e.g. a HMG-CoA reductase inhibitor (e.g. a statin).
  • a HMG-CoA reductase inhibitor e.g. a statin
  • the present invention also relates to a compound of formula I according to this invention or a pharmaceutically acceptable salt thereof for use in a method of primary or secondary prevention of cardiovascular diseases, particularly major cardiovascular events, optionally in combination with one or more other therapeutic agents, such as e.g. selected from those mentioned herein, such as e.g. a HMG-CoA reductase inhibitor (e.g. a statin).
  • a HMG-CoA reductase inhibitor e.g. a statin
  • the present invention also relates to processes and intermediates for preparing the compounds of general formula I according to the invention (see processes a, b, c and d in general synthesis section).
  • any and each of the above definitions a) (a 1 ) to f) (f 3 ) and/or a') (a 1' ) to f') (f 3' ) may be combined with one another.
  • Each a i , b i , c i , d i , e i , f i of a) to f) or of a') to f') represents a characterized, individual embodiment of the corresponding substituent as described above.
  • preferred individual embodiments of the compounds of formula I according to the invention are fully characterized by the term (a i b i c i d i e i f i ), wherein for each index i an individual figure is given and i ranges from 1 to the highest number given above; index 0 for each letter refers to the individual embodiment given at the outset of the part "Object of the invention".
  • Indices i vary independently from each other. All individual embodiments described by the term in parantheses with full permutation of the indices i, including i equals 0, referring to the definitions above, shall be comprised by the present invention.
  • Table 1 shows, exemplarily and in the order of increasing preference from the first line to the last line, such embodiments E-1 to E-12 of the compounds according to the invention that are considered preferred. This means that embodiment E-12, represented by the entries in the last row of Table 1, is the most preferred embodiment.
  • Table 2 also shows, exemplarily and in the order of increasing preference from the first line to the last line, such embodiments E-13 to E-24 of the compounds according to the invention that are considered preferred. This means that embodiment E-24, represented by the entries in the last row of Table 2, is the most preferred embodiment.
  • Another preferred embodiment of the compounds of formula I according to this invention refers to compounds of formula I* wherein the variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I*, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ) or a') (a 1' ) to f) (f 3' ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I* as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • this embodiment refers to compounds of formula I* as defined by the embodiment E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23 or E-24 in Table 2, and the salts thereof.
  • An embodiment of the compounds of formula I according to this invention refers to compounds of formula I** wherein the variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I**, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ) or a') (a 1' ) to f') (f 3' ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • this embodiment refers to compounds of formula I** as defined by the embodiment E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23 or E-24 in Table 2, and the salts thereof.
  • a preferred embodiment of the compounds of formula I according to this invention refers to compounds of formula I*** wherein the variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I***, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ) or a') (a 1' ) to f') (f 3' ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I*** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • this embodiment refers to compounds of formula I*** as defined by the embodiment E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23 or E-24 in Table 2, and the salts thereof.
  • a further embodiment of the compounds of formula I according to this invention refers to compounds of formula I**** wherein the variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I****, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ) or a') (a 1' ) to f') (f 3' ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I**** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • this embodiment refers to compounds of formula I**** as defined by the embodiment E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23 or E-24 in Table 2, and the salts thereof.
  • a more preferred embodiment of the compounds of formula I according to this invention refers to compounds of formula I***** wherein the variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I*****, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ) or a') (a 1' ) to f') (f 3' ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I***** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • this embodiment refers to compounds of formula I***** as defined by the embodiment E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23 or E-24 in Table 2, and the salts thereof.
  • the invention further includes all mixtures of the stereoisomers mentioned herein independent of the ratio, including the racemates.
  • a particularly preferred compound according to the invention is a compound selected from the group consisting of:
  • 1-nC-alkyl alone or as part of another group, wherein n may have a value of 1 to 6, denotes a saturated, branched or unbranched aliphatic, acyclic hydrocarbon group having 1 to n C atoms.
  • groups may include, without being limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • groups may include, without being limited to, ethenyl, prop-1-en-1-yl, prop-1-en-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-2-yl, etc..
  • halogen within the meaning of the present invention refers to fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are more worthy to be mentioned.
  • 1-nC-alkoxy denotes a 1-nC-alkyl-O- group, wherein 1-nC-alkyl is as hereinbefore defined.
  • groups may include, without being limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy, etc.
  • 1-nC-alkoxy-1-nC-alkyl means a 1-nC-alkyl group as defined herein which is substituted by a 1-nC-alkoxy group as defined herein.
  • cyano-1-nC-alkyl means a 1-nC-alkyl group as defined herein which is substituted by a cyano group.
  • hydroxy-1-nC-alkyl means a 1-nC-alkyl group as defined herein which is substituted by a hydroxy group.
  • aryl group as mentioned herein, alone or as part of another group refers to a carbocyclic, mono- or fused bicyclic (fully or partially) aromatic ring system having the indicated numbers of ring members.
  • Representative 6- or 10-membered mono- or fused bicyclic aryl groups include, without being limited to, phenyl and naphthyl.
  • a heteroaryl group as mentioned herein, alone or as part of another group, refers to a heterocyclic, mono- or fused bicyclic (fully or partially) heteroaromatic ring system having the indicated numbers of ring members and containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • Representative 5-membered monocyclic heteroaryl groups include, without being limited to, thiophenyl (thienyl), furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and oxadiazolyl,
  • 6-membered monocyclic heteroaryl groups include, without being limited to, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
  • Representative 9-membered fused bicyclic groups groups include, without being limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzpyrazolyl (indazolyl), benzthiazolyl, benzoxazolyl, benzisothiazolyl, and benzisooxazolyl.
  • Representative 10-membered fused bicyclic heteroaryl groups include, without being limited to, quinolyl, isoquinolyl, and quinazolyl.
  • thiophenyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and naphthyl are more worthy to be mentioned.
  • 3-nC-cycloalkyl alone or as part of another group, wherein n may have a value of 4 to 7, denotes a saturated, monocyclic, aliphatic hydrocarbon ring group having 3 to n ring C atoms.
  • groups may include, without being limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are more worthy to be mentioned.
  • 3-nC-cycloalkane alone or as part of another group, wherein n may have a value of 4 to 7, denotes a saturated, monocyclic, aliphatic hydrocarbon ring having 3 to n ring C atoms.
  • examples of such rings may include, without being limited to, a cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane ring, of which cyclopropane, cyclobutane, cyclopentane and cyclohexane are more worthy to be mentioned.
  • 1-nC-alkyl-3-nC-cycloalkyl means a 3-nC-cycloalkyl group as defined herein which is substituted by a 1-nC-alkyl group as defined herein.
  • cyano-3-nC-cycloalkyl means a 3-nC-cycloalkyl group as defined herein which is substituted by a cyano group.
  • Completely or partially fluorine-substituted 1-nC-alkyl is, for example difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoro-1-ethyl or 1,1,1,3,3,3-hexafluorisopropyl, of which trifluoromethyl is to be emphasized.
  • partially fluorine-substituted 1-nC-alkyl stands for predominantly fluorine-substituted 1-nC-alkyl. "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-nC-alkyl groups are replaced by fluorine atoms.
  • Completely or partially fluorine-substituted 1-nC-alkoxy is, for example difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,1,3,3,3-hexafluorisopropoxy.
  • partially fluorine-substituted 1-nC-alkoxy stands for predominantly fluorine-substituted 1-nC-alkoxy.
  • "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-nC-alkoxy groups are replaced by fluorine atoms.
  • heterocyclic groups mentioned herein include all the possible isomeric forms thereof, e.g. tautomers and/or positional isomers thereof.
  • pyridyl includes pyridine-2-yl, pyridine-3-yl and pyridine-4-yl.
  • carbocyclic groups which are substituted as mentioned herein may be substituted by their given substituents or parent molecular groups at any possible position.
  • heterocyclic groups mentioned herein may be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom.
  • rings containing quaternizable amino- or imino-type ring nitrogen atoms may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms.
  • the last named subgroup is the radical attachment point, for example, the substituent "1-nC-alkoxy-1-nC-alkyl” means a 1-nC-alkoxy group which is bound to a 1-nC-alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • All atoms/elements, including atoms that are part of a group, described herein comprise all stable isotopic forms of the respective element. For instance, whenever hydrogen is mentioned, either explicitly or as part of a group such as methyl, this includes hydrogen and deuterium as stable isotopic forms of the element hydrogen.
  • R 1 to R 8 , R 7' , PG, R a , R b , R 9 to R 11 are defined as above and below.
  • the substituents R 9 , R 10 and/or R 11 can be attached in the ortho, meta or para position with respect to the binding position in which the aryl ring is bonded to the scaffold ring system, whereby emphasis is given to the attachment in the meta or in the para position.
  • Salts of the compounds of formula I according to the present invention include - depending upon their nature - all acid addition salts and all salts with bases, especially all pharmaceutically acceptable acid addition salts and salts with bases. Particular mention may be made of the physiologically tolerable salts with inorganic or organic acids or bases customarily used in pharmacy.
  • the salts include water-insoluble and, particularly, watersoluble salts.
  • Inorganic acids suitable for forming pharmaceutically or physiologically acceptable acid addition salts include, by way of example and not limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like.
  • Organic acids suitable for forming pharmaceutically or physiologically acceptable acid addition salts include, by way of example and not limitation, citric acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, methanesulfonic acid, and the like.
  • pharmaceutically or physiologically acceptable acid addition salts with inorganic or organic acids include, by way of example and not limitation, hydrochlorides, hydrobromides, phosphates, sulfates, citrates, maleates, fumarates, succinates, lactates, tartrates, methanesulfonates (mesylates), and the like.
  • Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included.
  • the compounds of the present invention contain at least two asymmetrically substituted carbon atoms, and may be isolated as pure diastereomers or diastereomeric mixtures in optically active or racemic forms.
  • the compounds of formula I are chiral compounds having chiral centers at least in positions 3 and 9, as well as, depending on the meanings of R 3 and R 4 , in position 7, depending on the meanings of R 8 , in position 6 and, depending on the meanings of R 6 and R 7 , in position 1.
  • the invention contemplates all conceivable stereoisomers, particularly the diastereomers and enantiomers mentioned herein, e.g. in substantially pure form, in enriched form (e.g. substantially free of any or all other undesired diastereomers and/or enantiomers) and/or in any mixing ratio, including the racemic forms, as well as the salts thereof.
  • substantially pure stereoisomers can be obtained according to synthetic principles customary to the skilled person, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis.
  • optically active forms such as by resolution of racemic forms or by synthesis, e.g. from optically active starting materials and/or by using chiral reagents.
  • Enantiomerically pure compounds of this invention can be prepared via asymmetric synthesis, for example by preparation and separation of appropriate diastereoisomeric compounds/intermediates which can be separated by known methods (e.g. by chromatographic separation or (fractional) crystallization from a suitable solvent), and/or by using chiral reaction components (e.g. chiral reagents, chiral catalysts, chiral ligands, chiral synthons, chiral building blocks, or the like).
  • chiral reaction components e.g. chiral reagents, chiral catalysts, chiral ligands, chiral synthons, chiral building blocks, or the like.
  • the biological properties of the new compounds may be investigated as follows:
  • CETP inhibitory activity of compounds of the present invention can be determined in a fluorometric assay puchased from Roar Biomedical, Inc. (New York, N.Y., USA).
  • the compounds of the present invention inhibit CETP-dependent cholesterol ester transfer from HDL to LDL as described here.
  • Recombinant human CETP was partially purified from medium conditioned by CETP expressing CHO cells. In a 384 well format 2.5 ⁇ l of compound solution in DMSO was combined with 2 ⁇ l of donor solution, 2 ⁇ l of acceptor solution and 0.8 ⁇ l of recombinant human CETP solution in a total volume of 100 ⁇ l with assay buffer and incubated for 3 hours at 37°C. The fluorescence intensity was measured at excitation wavelenght of 485 nm and emission wavelenght of 535 nm. IC 50 values are calculated from dose effect curves from compound concentrations between 1 nM and 30 ⁇ M.
  • the compounds of general formula I according to the invention for example have IC 50 values below 10000 nM, preferably below 2000 nM, more preferably below 400 nM and most preferably below 100 nM.
  • the IC 50 values of the examples compiled in the experimental part are provided in the following Table 2.
  • Table 2 IC 50 values for inhibition of CETP by the examples compiled in the experimental part
  • Example IC 50 [nM] Example IC 50 [nM]
  • Example IC 50 [nM] Example IC 50 [nM] 1 54 1(37) 418 1(61) 66 1(1) 1433 4 62 1(62) 21 1(2) 4682 1(38) 3315 1(63) 6 2 (Diastereomer 1) 699 1(39) 56 1(64) 86 1(3) 460 1(40) 37 1(65) 83 1(4) 45 1(41) 524 1(66) 34 1(5) 42 1(42) 25 1(67) 161 1(6) 37 1(43) 22 1(68) 24 1(7) 77 1(44) 69 1(69) 14 1(8) 856 1(45) 122 4(8) 14 1(9) 148 1(46) 1835 1(70) 57 1(10) 360 1(47) 136 1(71) 31 1(11) 36 4(1) 127 1(80) 47 1(12) 150 4
  • the compounds of formula I and their physiologically tolerable salts according to the present invention have valuable pharmacological properties which make them commercially applicable.
  • these compounds can act as inhibitors of CETP and are expected to be commercially applicable in the therapy of diseases responsive to the inhibition of CETP, such as e.g. any of those diseases mentioned herein.
  • the compounds of general formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for the treatment and/or prevention of all those conditions or diseases which may be affected by the inhibition of the cholesterol ester transfer protein (CETP) activity. Therefore, compounds according to the invention are particularly suitable for the treatment and/or prevention of cardiovascular and/or cardiometabolic and related disorders, in particular atherosclerosis, peripheral vascular disease, dyslipidemia (including e.g.
  • hyperbeta-lipoproteinemia hyperalpha-lipoproteinemia
  • hypercholesterolemia hypertriglyceridemia
  • hyperlipidemia hypolipoproteinemia
  • hyperlipoproteinemia hypo-HDL cholesterolemia
  • hyper-LDL cholesterolemia familial hypercholesterolemia
  • angina ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, endothelial dysfunction, vascular complications of diabetes, prevention of diabetes, insulin resistance, obesity, metabolic syndrome, diabetes (especially type 2 diabetes meliitus) or endotoxemia, or arteriosclerosis, coronary heart disease, coronary artery disease, coronary vascular disease or congestive heart failure.
  • the compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral, parenteral or topical administration. They may be administered in any of the generally accepted modes of administration available in the art, e.g., perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally (including intravenously), e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
  • oral and intravenous delivery are preferred.
  • compositions such as e.g. diluents, carriers, binders, disintegrants, surfactants, lubricants, vehicles, auxiliaries, adjuvants and/or further additives which are known to be suitable for preparing pharmaceutical compositions, on account of his/her expert knowledge.
  • excipients such as e.g. diluents, carriers, binders, disintegrants, surfactants, lubricants, vehicles, auxiliaries, adjuvants and/or further additives which are known to be suitable for preparing pharmaceutical compositions, on account of his/her expert knowledge.
  • any excipients known to be appropriate for pharmaceutical compositions come into consideration.
  • examples thereof include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, glidants, solvents, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, thickeners, complexing agents, buffers, pH regulators (e.g. to obtain neutral, alkaline or acidic formulations), permeation promoters, polymers, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.
  • diluents fillers, binders, disintegrants, lubricants, glidants, solvents, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, thickeners,
  • suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, starches (e.g. corn starch) or derivatives thereof, talc, silica, polyvinylpyrrolidones, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, e.g., vegetable oils, waxes, fats and semi-solid and liquid polyols.
  • Suitable carrier materials for the production of solutions and syrups are, e.g., water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injection or infusion solutions are, e.g., water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, e.g., natural or hardened oils, waxes, fats and semi-liquid or liquid polyols or polyethylene glycols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • excipients, carriers and/or diluents of a type appropriate to the desired pharmaceutical composition, formulation or preparation and the desired mode of administration are used.
  • compositions according to this invention can be prepared by processes which are known per se and familiar to the person skilled in the art, e.g. by incorporating the described compounds of formula I or their pharmaceutically acceptable salts (optionally combined with other active substances) optionally together with one or more conventional carriers (e.g. solid or liquid carriers) and/or diluents, e.g.
  • conventional carriers e.g. solid or liquid carriers
  • diluents e.g.
  • the dosage of the compounds of the invention can vary within wide limits depending on the compound which is to be administered, the nature and gravity of the disease to be treated or prevented, the age and the individual condition of the patient and the mode and frequency of administration, and will, of course, be fitted to the individual requirements in each particular case.
  • the dosage may be from 0.1 ng/ml to 10 mg/ml, preferably 1 ng/ml to 10 mg/ml, by intravenous route, and 0.1 to 2000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day.
  • the dosage may be convenient to administer the daily dosage in several dosage units.
  • the compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases, disorders and conditions mentioned above.
  • active substances which are suitable for such a combination include for example those which potentiate the therapeutic effect of a cholesterol ester transfer protein (CETP) inhibitor according to the invention with respect to one of the indications mentioned and/or which allow the dosage of a cholesterol ester transfer protein (CETP) inhibitor according to the invention to be reduced.
  • CETP cholesterol ester transfer protein
  • Lipid modulating agents comprise HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR ( ⁇ , ⁇ or ⁇ / ⁇ ) agonists or modulators, ACAT inhibitors (e.g. avasimibe), MTP inhibitors, squalene cyclase and squalene synthase inhibitors, LXR agonists or modulators, bile acid-binding substances such (e.g. cholestyramine, colesevelam), cholesterol absorption inhibitors (e.g. ezetimibe), niacin, PCSK9 inhibitors, bile acid reuptake inhibitors and lipase inhibitors.
  • HMG CoA reductase inhibitors e.g. simvastatin, atorvastatin
  • fibrates e.g.
  • therapeutic agents which are suitable for such a combination include one or more antidiabetic agents as for example metformin, alpha-glucosidase inhibitors (e.g. acarbose, voglibose), PPAR ( ⁇ , ⁇ or ⁇ / ⁇ ) agonists or modulators, DPP-IV inhibitors (e.g. Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin), SGLT 2 inhibitors (e.g. dapagliflozin, sergliflozin), GLP-1 or GLP-1 analogues (e.g.
  • antidiabetic agents as for example metformin, alpha-glucosidase inhibitors (e.g. acarbose, voglibose), PPAR ( ⁇ , ⁇ or ⁇ / ⁇ ) agonists or modulators, DPP-IV inhibitors (e.g. Sitagliptin, Vild
  • exenatide liraglutide
  • insulin or insulin analogues e.g. sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), thiazolidinediones (e.g.
  • antiobesity agents including for example sibutramine, tetrahydrolipostatin, leptin, leptin mimetics, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ⁇ 3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
  • drugs for influencing high blood pressure or chronic heart failure such as e.g. A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ -blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
  • angiotensin II receptor antagonists examples include candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc.
  • Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
  • the therapeutic agents mentioned herein above as combination partners of the compounds according to this invention are meant to include pharmaceutically acceptable derivatives thereof, such as e.g. their pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivatives thereof such as e.g. their pharmaceutically acceptable salts.
  • the person skilled in the art is aware on the base of his/her expert knowledge of the kind, total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range.
  • the dosage for the combination partners mentioned above is 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
  • the compounds according to this invention may be administered in combination therapy separately, sequentially, simultaneously, concurrently or chronologically staggered with one or more further active substances, such as e.g. any of the therapeutic agents mentioned herein above as a combination partner.
  • the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one of the active substances described above as a combination partner, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy, particularly for treatment and/or prevention of cardiovascular or related disorders, such as e.g. any of those mentioned herein.
  • this invention relates to the use of a compound according to this invention combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which may be affected by the inhibition of the cholesterol ester transfer protein (CETP) activity, particularly cardiometabolic and/or cardiovascular disorders, more particularly one of the diseases, disorders or conditions listed above.
  • CETP cholesterol ester transfer protein
  • this invention relates to a pharmaceutical composition which comprises a compound according to the invention and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
  • combination may be present as a fixed combination, a non-fixed combination, a free combination or a kit-of-parts.
  • a “fixed combination” is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration.
  • Another example of a “fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a “kit-of-parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the first and second active ingredient of a kit-of-parts according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy.
  • the type of pharmaceutical formulation of the first and second active ingredient of a kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration.
  • the amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount, particularly for the treatment and/or prevention of the diseases, disorders and conditions mentioned above.
  • the compounds according to the invention may be obtained using methods of synthesis known in principle.
  • the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.
  • First step is the condensation of triester of formula II, wherein each R a denotes independently methyl or ethyl (preferably all R a are identical) with enaminoketones of formula III.
  • This reaction is usually carried out neat at temperatures between 150°C and 250°C, and yields the bicyclic dihydroxypyridines of formula IV .
  • Compounds of formula V can be converted in compounds of formula VI by installing the R 2 group via a carbon-carbon-coupling reaction, preferably either by a Negishi reaction or by a Suzuki reaction.
  • Negishi reaction compounds of formula V are reacted with suitable (cyclo)alkyl-zinc-halogenide reagents or (cyclo)alkenyl-zinc-halogenide reagents of formula R 2 -ZnX, wherein X is a halogen (e.g. chlorine) in a suitable solvent such as e.g. toluene, tetrahydrofurane, 1,4-dioxane or diethylether in the presence of a suitable catalyst such as e.g.
  • a suitable solvent such as e.g. toluene, tetrahydrofurane, 1,4-dioxane or diethylether
  • a suitable catalyst such as e.g.
  • a palladium source like e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0) and a suitable ligand like e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 40°C and 180°C, but preferably between 70°C and 130°C.
  • the (cyclo)alkyl-zinc-halogenide reagents or (cyclo)alkenyl-zinc-halogenide reagents can optionally be prepared by transmetalation of corresponding (cyclo)alkyl-magnesium-halogenide reagents or (cyclo)alkenyl-magnesium-halogenide reagents, e.g. with zinc chloride in diethylether, tetrahydrofurane or 1,4-dioxane.
  • the Suzuki reaction is performed by reacting compounds of formula V with a suitable R 2 -borone reagent, such as e.g.
  • aqueous sodium carbonate aqueous potassium carbonate, aqueous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine and in the presence of a suitable catalyst such as e.g.
  • a palladium source like e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0) and a suitable ligand like e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 0°C and 180°C, but preferably between room temperature and 120°C.
  • reaction is proceeded by a reduction of the double bond.
  • a suitable catalyst such as e.g. palladium on charcoal or palladiumhydroxide on charcoal in a suitable solvent such as e.g.
  • methanol ethanol, ethylacetate, tetrahydrofurane or 1,4-dioxane but preferably methanol, at temperatures between -20°C and 100°C but preferably between 0°C and 80°C.
  • 1-3C-perfluoroalkyl reagent such as e.g. 1-3C-perfluoroalkyl-iodide, 1-3C-perfluoroalkyl-trimethylsilane, potassium 1-3C-perfluoroalkyl-carboxylate or methyl 2,2-difluoro-2-(fluorosulfonyl)-acetate
  • a suitable solvent such as e.g. N,N-dimethylformamide, N-methylpyrrolidone or dimethylsulfoxide
  • a suitable catalyst such as e.g.
  • Transformation of compounds of formula VI wherein R b denotes hydroxyl in compounds of formula VI wherein R b denotes chlorine is done by reacting with phosphoroxychloride and catalytic amounts of N,N-dimethylformamide, at temperatures between 50°C and 150°C but preferably between 70°C and 120°C.
  • R b denotes iodine
  • a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g.
  • alkylation reaction of compounds of formula VI wherein R b denotes iodine with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (-)-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3
  • the alcohol group in compounds of formula VII can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give the protected derivatives of formula VIII, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C
  • This protection can also be carried out by reacting compounds of formula VII with tert.-butyldimethylsilyl-trifluormethansulfonate in the presence of a suitable base such as e.g. pyridine or 2,6-lutidine in a suitable solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -50°C and 100°C but preferably between -30°C and 50°C.
  • a suitable protecting group as described e.g. in " Protective Groups in Organic Synthesis", 2nd edition, Greene T. W., Wuts P. G. M.; Wiley-Interscience: New York, 1991 or in " Protective Groups", Kocienski P. J.; Thieme: New York, 1994 can be used.
  • the esters of formula VIII can be converted to the aldehydes of formula IX, e.g. by a two step sequence.
  • First step is the reduction to the alcohol with a suitable reducing agent, such as e.g. diisobutylaluminium hydride or lithiumaluminiumhydride in an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between - 78°C and 100°C, but preferably between -30°C and 50°C.
  • Second step is the oxidation of the alcohol to the aldehyde, which can be carried out with Dess-Martin-Periodinan (J. Chem. Soc.
  • this transformation can be performed by reaction with RuCl 3 or tetrapropylammonium perrhutenate in the presence of N-methylmorpholin-N-oxyde in acetonitrile or dichlormethane, or by an oxidation catalysed by 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) in the presence of iodine and a base as for example sodium bicarbonate in a solvent such as e.g.
  • TEMPO 2,2,6,6-tetramethyl-piperidin-1-oxyl
  • dichloromethane tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between -30°C and 80°C but preferably between 0°C and 40°C.
  • Aldehydes of formula IX are transformed to the alcohols of formula X by reaction with a suitable R 1 -metal reagent, such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent, in an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -78°C and 80°C, but preferably between -50°C and 40°C.
  • a suitable R 1 -metal reagent such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent
  • an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • aqueous sodium carbonate aqueous potassium carbonate, aqueous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine but preferably caesium fluoride and in the presence of a suitable catalyst such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 0°C and 180°C, but preferably between room temperature and 120°C, gives compounds of formula XI.
  • These compounds of formula XII are reduced to the compounds of formula XIII with a suitable reducing agent, such as e.g. tris-trimethylsilylsilane or tributyltin hydride in the presence of a suitable radical starter such as e.g. azo-bis-isobutyronitrile or dibenzoylperoxide in a suitable solvent such as e.g. carbontetrachloride, benzene or toluene,-at temperatures between 80°C and 150°C.
  • a suitable reducing agent such as e.g. tris-trimethylsilylsilane or tributyltin hydride
  • a suitable radical starter such as e.g. azo-bis-isobutyronitrile or dibenzoylperoxide
  • a suitable solvent such as e.g. carbontetrachloride, benzene or toluene
  • a suitable solvent such as e.g. methanol, ethanol, tetrahydrofurane or 1,4-dioxane but preferably methanol.
  • This reaction may be carried out in the presence of a suitable base such as e.g. triethylamine or N,N-diisopropyl-N-ethyl-amine, at temperatures between -20°C and 100°C but preferably between 0°C and 80°C.
  • a suitable base such as e.g. triethylamine or N,N-diisopropyl-N-ethyl-amine
  • a suitable hydrogen source such as e.g. Et 3 SiH in the presence of F 3 CCO 2 H.
  • First step is the formation of N-oxides of formula XV.
  • This reaction is performed by treating compounds of formula XIV with a suitable oxidizing reagent, such as e.g. meta-chloroperbenzoic acid (MCPBA), in a suitable solvent such as e.g. dichloromethane, 1,2-dichloroethane, chloroform or tetrachloromethane, at temperatures between -10°C and 60°C.
  • MCPBA meta-chloroperbenzoic acid
  • a suitable solvent such as e.g. dichloromethane, 1,2-dichloroethane, chloroform or tetrachloromethane, at temperatures between -10°C and 60°C.
  • Compounds of formula XV are then reacted with acetic acid anhydride or propionic acid anhydride at temperatures between 90°C and 180°C to deliver compounds of formula XIII, wherein R 8 denotes acetoxy or propionyl
  • a suitable base such as e.g. sodium carbonate, potassium carbonate, caesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent
  • a suitable solvent such as e.g. methanol, ethanol, tetrahydrofurane, water or in a mixture of water and methanol or ethanol
  • these compounds of formula XIII, wherein the -OPG group and the R 8 residue are cis configured can be treated with a suitable base such as e.g. sodium carbonate, potassium carbonate, caesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent like methanol, ethanol or water or in a mixture of water and methanol or ethanol, at temperatures between 0°C and 80°C, to deliver directly compounds of ormula I, wherein R 8 denotes hydroxy.
  • a suitable base such as e.g. sodium carbonate, potassium carbonate, caesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent like methanol, ethanol or water or in a mixture of water and methanol or ethanol, at temperatures between 0°C and 80°C, to deliver directly compounds of ormula I, wherein R 8 denotes hydroxy.
  • compounds of formula VIII can be prepared according to the invention related process c) shown in scheme 3, wherein R a , R 2 , R 3 ,R 4 and R 5 are defined as described before and R 8 denotes hydrogen, starting from compounds of formula V, wherein R b denotes chlorine.
  • compounds of formula V wherein R b denotes chlorine, are converted into compounds of formula XVI by reacting with a suitable iodination reagent such as e.g. sodium iodide and acetylchloride in a suitable solvent such as e.g. acetonitrile, N,N-dimethylformamide, 1,4-dioxane or tetrahydrofurane but preferably in acetonitrile, at temperatures between 0°C and 100°C but preferably between room temperature and 80°C.
  • a suitable iodination reagent such as e.g. sodium iodide and acetylchloride
  • a suitable solvent such as e.g. acetonitrile, N,N-dimethylformamide, 1,4-dioxane or tetrahydrofurane but preferably in acetonitrile
  • a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g.
  • alkylation reaction of compounds of formula XVI wherein R b denotes iodine with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (-)-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3
  • the alcohol group in compounds of formula XVII can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give the protected derivatives of formula XVIII, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but
  • This protection can also be carried out by reacting compounds of formula XVII with tert.-butyldimethylsilyl-trifluormethansulfonate in the presence of a suitable base such as e.g. pyridine or 2,6-lutidine in a suitable solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -50°C and 100°C but preferably between -30°C and 50°C.
  • any other suitable protecting group as described e.g. in " Protective Groups in Organic Synthesis", 2nd edition, Greene T. W., Wuts P. G. M.; Wiley-Interscience: New York, 1991 or in " Protective Groups", Kocienski P. J.; Thieme: New York, 1994 can be used.
  • a suitable solvent such as e.g. toluene, tetrahydrofurane, 1,4-dioxane or diethylether
  • a suitable catalyst such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 40°C and 180°C, but preferably between 70°C and 130°C, delivers compounds of formula VIII.
  • the (cyclo)alkyl-zinc-halogenide reagents may optionally be prepared by transmetalation of corresponding (cyclo)alkyl-magnesium-halogenide reagents, e.g. with zinc chloride in diethylether, tetrahydrofurane or 1,4-dioxane.
  • a suitable base such as e.g aqueous sodium carbonate, aqueous potassium carbonate, aqueous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine but preferably caesium fluoride
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 0°C and 180°C, but preferably between room temperature and 120°C, gives compounds of formula XIX.
  • a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g.
  • borane reagents such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex or borane-diethylaniline-complex each in the presence of (1 R,2S)-(+)-cis-1-Amino-2-indanole gives compounds of formula XX with S-configuration at the newly formed stereocenter as is known from the literature (see Tetrahedron: Asymmetry 1995, 6, 301-306 ; Synthesis 1998, 937-961 or Angew. Chem. 1999, 111, 3574-3576 ).
  • borane reagents such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex or borane-diethylaniline-complex
  • alkylation reaction of compounds of formula XIX with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • the alcohol group in compounds of formula XX can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a solvent such as e.g. dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give the protected derivatives of formula XXI, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a solvent such as e.g. dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give
  • This protection can also be carried out by reacting compounds of formula XX with tert.-butyldimethylsilyl-trifluormethansulfonat in the presence of a base such as e.g. pyridine or 2,6-lutidine in a solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -50°C and 100°C but preferably between -30°C and 50°C.
  • a base such as e.g. pyridine or 2,6-lutidine
  • a solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • any other suitable protecting group as described e.g. in " Protective Groups in Organic Synthesis", 2nd edition, Greene T. W., Wuts P. G. M
  • the esters of formula XXI can be converted to the aldehydes of formula XXII e.g. by a two step sequence.
  • First step is the reduction to the alcohol with a suitable reducing agent, such as e.g. diisobutylamuminium hydride of lithiumaluminiumhydride in an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between.-78°C and 100°C, but preferably between -30°C and 50°C.
  • Second step is the oxidation of the alcohol to the aldehyde which can be carried out with Dess-Martin-Periodinan ( J.
  • this transformation can be performed by reaction with RuCl 3 or tetrapropylammonium perrhutenate in the presence of N-methylmorpholin-N-oxyde in acetonitrile or dichlormethane, or by an oxidation catalysed by 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) in the presence of iodine and a base as for example sodium bicarbonate in a solvent like dichloromethane, tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between -30°C and 80°C but preferably between 0°C and 40°C.
  • TEMPO 2,2,6,6-tetramethyl-piperidin-1-oxyl
  • Aldehydes of formula XXII are transformed to the alcohols of formula XI by reaction with a suitable R 1 -metal reagent, such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent, in an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -78°C and 80°C, but preferably between -50°C and 40°C.
  • a suitable R 1 -metal reagent such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent
  • an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • First step is the addition of alkynes of formula XXIII to aldehydes of formula XXIV.
  • the alkyne is deprotonated with an organometalspecies such as e.g. n-butyllithium, sec.-butyllithium, tert.-butyllithium, methylmagnesium bromide, ethylmagnesiumbromide or isopropylmagnesium chloride, but preferably n-butyllithium, in a solvent such as e.g.
  • a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine or 2,6-lutidine
  • an acylation catalyst such as 4-dimethylamino-pyridine (DMAP), in a solvent such as e.g.
  • esters of formula XXVI are then reacted with alcohols of formula XXVII in the presence of an acid such as e.g. methylsulfonic acid or trifluoromethylsulfonic acid or in the presence of a Lewis acid such as e.g.
  • trimethylsilyl-trifluoromethanesulfonate triethylsilyl- trifluoromethanesulfonate or tert.-butyldimethylsilyl-trifluormethansulfonate, but preferably trimethylsilyl-trifluoromethanesulfonate, in a solvent such as e.g. dichloromethane or 1,2-dichloroethane, at temperatures between -50°C and room temperature but preferably between -40°C and 0°C to give ethers of formula XXVIII. These ethers are then deprotonated with an organometalspecies such as e.g.
  • a solvent such as e.g. diethylether, tetrahydrofurane or 1,4-dioxane at temperatures between -78°C and 0°C, but preferably between -78°C and -20°C.
  • the metal-alkyne is reacted with carbonyl compounds of formula XXIX at temperatures between -78°C and 0°C to give compounds of formula XXX.
  • a catalyst such as e.g. cyclopentadienyl-cobalt-dicarbonyl, cyclopentadienyl-cobalt-diethylen-complex, bis-(1,5-cyclooctadien)-rhodium-(I)-tetrafluoroborate or bis-(1,5-cyclooctadien)-rhodium-(I)-trifluoromethanesulfonate, but preferably cyclopentadienyl-cobalt-dicarbonyl, for the rhodium-catalysts additionally in the presence of a ligand such as e.g.
  • toluene, xylene, 1,2-dichloroethane or diphenylether but preferably in toluene, at temperatures between 80°C and 180°C to give compounds of formula I.
  • this reaction can be performed thermally either neat or in a suitable solvent such as e.g. toluene, xylene or diphenylether at temperatures between 150°C and 250°C.
  • the alcohol group in compounds of formula XXX can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g.
  • N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give the protected derivatives of formula XXXI, in which PG stands for this suitable protecting group.
  • This protection can also be carried out by reacting compounds of formula XXX with tert.-butyldimethylsilyl-trifluormethansulfonate in the presence of a suitable base such as e.g. pyridine or 2,6-lutidine in a suitable solvent such as e.g.
  • cyclopentadienyl-cobalt-dicarbonyl cyclopentadienyl-cobalt-diethylen-complex, bis-(1,5-cyclooctadien)-rhodium-(I)-tetrafluoroborate or bis-(1,5-cyclooctadien)-rhodium-(I)-trifluoromethanesulfonate, but preferably cyclopentadienyl-cobalt-dicarbonyl, for the rhodium-catalysts additionally in the presence of a ligand such as e.g.
  • the alcohol group in compounds of formula I can be protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a solvent such as e.g. dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give the protected derivatives of formula XIII, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a solvent such as e.g. dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between -20°C and 120°C, but preferably between 0°C and 80°C, to give the protected derivatives
  • This protection can also be carried out by reacting compounds of formula I with tert.-butyldimethylsilyl-trifluormethansulfonate in the presence of a base such as e.g. pyridine or 2,6-lutidine in a solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -50°C and 100°C but preferably between -30°C and 50°C.
  • a base such as e.g. pyridine or 2,6-lutidine
  • a solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • any other suitable protecting group as described e.g. in " Protective Groups in Organic Synthesis", 2nd edition, Greene T. W., Wuts P. G.
  • Carbonyl compounds of formula XXIX, wherein R 3 -R 5 are defined as hereinbefore, R 8 denotes hydrogen, can be carried out according to the invention related process f) shown in scheme 6.
  • First step is the reduction of malonates of formula XXXII, wherein R a denotes independently methyl or ethyl, to diols of formula XXXIII with a suitable reducing agent, such as e.g. diisobutylamuminium hydride or lithiumaluminiumhydride in an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -78°C and 80°C, but preferably between -30°C and 50°C.
  • a suitable reducing agent such as e.g. diisobutylamuminium hydride or lithiumaluminiumhydride
  • an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene
  • Diols of formula XXXIII are then transformed into cyclic sulfites of formula XXXIV by reaction with thionylchloride, optionally in the presence of a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine or pyridine, in dichloromethane at temperatures between 0°C and 50°C. Further reaction with sodium cyanide or potassium cyanide e.g. in dimethylsulfoxide or N,N-dimethylformamide at temperatures between 80°C and 150°C gives compounds of formula XXXV.
  • a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine or pyridine
  • this transformation can be performed by reaction with RuCl 3 or tetrapropylammonium perrhutenate in the presence of N-methylmorpholin-N-oxyde in acetonitrile or dichlormethane, or by an oxidation catalysed by 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) in the presence of iodine and a base such as e.g. sodium bicarbonate in a solvent such as e.g.
  • TEMPO 2,2,6,6-tetramethyl-piperidin-1-oxyl
  • 1-4C-alkylmagnesium halogenide- or 1-4C-alkyllithium-reagent in a suitable solvent such as e.g. diethylether, tetrahydrofurane or 1,4-dioxane, at temperatures between -78°C and room temperature gives the alcohols of formula XXXIX, wherein R 5 denotes 1-4C-alkyl, particularly 1-2C-alkyl.
  • dichloromethane tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between -30°C and 80°C but preferably between 0°C and 40°.
  • a solvent such as e.g. dichloromethane or 1,2-dichloroethane.
  • a solvent such as e.g. diethylether, tetrahydrofurane or 1,4-dioxane at temperatures between -78°C and 0°C, but preferably between -78°C and -20°C.
  • the metal-alkyne is reacted with aldehydes of formula XXXVIII at temperatures between -78°C and room temperature to give compounds of formula XLII.
  • a catalyst such as e.g. cyclopentadienyl-cobalt-dicarbonyl, cyclopentadienyl-cobalt-diethylen-complex, bis-(1,5-cyclooctadien)-rhodium-(I)-tetrafluoroborate or bis-(1,5-cyclooctadien)-rhodium-(I)-trifluoromethanesulfonate, but preferably cyclopentadienyl-cobalt-dicarbonyl, for the rhodium-catalysts additionally in the presence of a ligand such as e.g.
  • this transformation can be performed by reaction with RuCl 3 or tetrapropylammonium perrhutenate in the presence of N-methylmorpholin-N-oxyde in acetonitrile or dichlormethane, or by an oxidation catalysed by 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) in the presence of iodine and a base such as e.g. sodium bicarbonate in a solvent such as e.g.
  • TEMPO 2,2,6,6-tetramethyl-piperidin-1-oxyl
  • dichloromethane tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between -30°C and 80°C but preferably between 0°C and 40°.
  • Cleavage of the silylacetal group in XLIV with tetrabutylammonium fluoride in tetrahydrofurane at temperatures between -10°C and room temperature gives compounds of formula XLV.
  • Cyclisation to compounds of formula XLVI can then perfomed by reaction with diethylamino-sulfur-trifluoride (DAST) or bis-(2-methoxyethyl)-amino-sulfur-trifluoride (BAST) in a aprotic solvent such as e.g. dichloromethane or 1,2-dichloroethane at temperatures between -30°C and 50°C.
  • DAST diethylamino-sulfur-trifluoride
  • BAST bis-(2-methoxyethyl)-amino-sulfur-trifluoride
  • borane-tetrahydrofurane-complex borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g.
  • alkylation reaction of compounds of formula XLVI with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand such as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (-)-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand such as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-
  • ketoesters of formula XLVIII wherein R a denotes methyl or ethyl
  • a suitable solvent such as e.g. methanol or ethanol
  • a suitable base such as e.g. sodium ethoxide or sodium methoxide
  • epoxides of formula XLVII at temparatures between -10°C and 80°C to give ketolactones XLIX.
  • Ketolactones XLIX are oxidized to furanones L with a suitable oxidizing reagent such as e.g. 2-iodoxybenzoic acid and 4-methoxypyridine-N-oxide in a suitable solvent such as e.g.
  • Furanones of formula L are condensed with enaminoketones of formula III, e.g. at temperatures between 150°C and 250°C either neat under reduced pressure at or at temperatures between 100°C and 150°C in a suitable solvent such as e.g. acetic acid yielding the tricyclic dihydropyridines of formula LI.
  • Dihydropyridines LI are oxidized to the corresponding tricyclic pyridines of formula LII using a suitable oxidizing reagent such as e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a suitable solvent such as e.g. dichloromethane at temperatures between 0°C and 50°C.
  • a suitable oxidizing reagent such as e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a suitable solvent such as e.g. dichloromethane at temperatures between 0°C and 50°C.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • solvent such as e.g. dichloromethane
  • Reduction of the ketogroup in tricyclic pyridines of formula LII is carried out with a suitable hydride donating reagent
  • borane-tetrahydrofurane-complex borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g.
  • alkylation reaction of compounds of formula LII with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand such as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (-)-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand such as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-
  • R 1 -magnesium halogenide- or R 1 -lithium-reagent in an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -78°C and room temperature for lithium reagents or between -50°C and room temperature for magnesium reagents.
  • the lactols of formula LV are reduced to the corresponding compounds of formula XIII using a combination of a suitable acid such as e.g. titaniumtetrachloride or borontrifluoride etherate with a suitable hydride donating reagent such as e.g.
  • malonesters of formula LVI wherein R a denotes independently methyl or ethyl
  • a suitable solvent such as e.g. methanol or ethanol
  • a suitable base such as e.g. sodium ethoxide or sodium methoxide and treated with epoxides of formula XLVII at temparatures between -10°C and 80°C to give lactones LVII.
  • the lactones LVII are oxidized to furanones LVIII with a suitable oxidizing reagent such as e.g. 2-iodoxybenzoic acid and 4-methoxypyridine-N-oxide in a suitable solvent such as e.g. dimethylsulfoxide at temperatures between 0°C and 50°C.
  • a suitable oxidizing reagent such as e.g. 2-iodoxybenzoic acid and 4-methoxypyridine-N-oxide
  • a suitable solvent such as e.g. dimethylsulfoxide at temperatures between 0°C and 50°C.
  • Furanones of formula LVIII are condensed with enaminoketones of formula III, e.g. at temperatures between 150°C and 250°C either neat under reduced pressure at or at temperatures between 100°C and 150°C in a suitable solvent such as e.g. acetic acid yielding the tricyclic hydroxo dihydropyridines of formula LIX.
  • the hydroxo dihydropyridines LIX are oxidized to the corresponding tricyclic hydroxy pyridines of formula LX using a suitable oxidizing reagent such as e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a suitable solvent such as e.g. dichloromethane at temperatures between 0°C and 50°C.
  • a suitable oxidizing reagent such as e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a suitable solvent such as e.g. dichloromethane at temperatures between 0°C and 50°C.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • a suitable solvent such as e.g. dichloromethane
  • pyridines of formula LXI chlorination of hydroxy pyridines of formula LX with phosphoroxychloride and catalytic amounts of N,N-dimethylformamide at 45°C gives pyridines of formula LXI, wherein R b denotes chlorine.
  • Reduction of the ketogroup in pyridines of formula LXI is carried out with a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g.
  • alkylation reaction of compounds of formula LXI with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (-)-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3
  • R 1 -magnesium halogenide- or R 1 -lithium-reagent in an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between -78°C and room temperature for lithium reagents or between -50°C and room temperature for magnesium reagents.
  • the lactols of formula LXIV are reduced to the corresponding compounds of formula LXV using a combination of a suitable acid such as e.g. titaniumtetrachloride or borontrifluoride etherate with a suitable hydride donating reagent such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 0°C and 80°C, but preferably at room temperature, delivering compounds of formula LXVII.
  • a suitable base such as e.g aqueous sodium carbonate, aqueous potassium carbonate, aqueous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine but preferably caesium fluoride
  • a suitable palladium source such as e.g. palladium diacetate or tris-(dibenzyiideneacetone)-dipalladium-(0)
  • a suitable ligand such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, at temperatures between 0°C and 180°C, but preferably between room temperature or 120°C.
  • Compounds of formula LXVII can be reduced to compounds of formula XIII by hydrogenation in the presence of a suitable catalyst such as e.g. palladium on charcoal or palladiumhydroxide on charcoal in a suitable solvent such as e.g. methanol, ethanol, tetrahydrofurane or 1,4-dioxane.
  • a suitable catalyst such as e.g. palladium on charcoal or palladiumhydroxide on charcoal in a suitable solvent such as e.g. methanol, ethanol, tetrahydrofurane or 1,4-dioxane.
  • This reaction may be carried out under hydrogen pressures between 1 bar and 3 bar, optionally in the presence of a suitable base such as e.g. triethylamine or N,N-diisopropyl-N-ethyl-amine, at temperatures between 0°C and 80°C but preferably with palladium on charcoal in methanol under 3 bar hydrogen pressure at room temperature.
  • Compounds of formula LXVIII are reduced to compounds of formula XIII by hydrogenation in the presence of a suitable catalyst such as e.g. palladium on charcoal, palladiumhydroxide on charcoal or platinumdioxide in a suitable solvent such as e.g. acetic acid, methanol, ethanol, tetrahydrofurane or 1,4-dioxane but preferably acetic acid.
  • a suitable catalyst such as e.g. palladium on charcoal, palladiumhydroxide on charcoal or platinumdioxide in a suitable solvent such as e.g. acetic acid, methanol, ethanol, tetrahydrofurane or 1,4-dioxane but preferably acetic acid.
  • a suitable solvent such as e.g. acetic acid, methanol, ethanol, tetrahydrofurane or 1,4-dioxane but preferably acetic acid.
  • compounds of formula LXVII can be transformed into compounds of formula LXIX, wherein R 2''' denotes hydrogen by ozonolysis in a suitable solvent such as e.g. dichloromethane at temperatures between -80°C and -40°C and subsequent treatment with a suitable reducing agent such as e.g. sodium borohydride in a suitable solvent such as e.g. methanol or ethanol at temperatures between 0°C and room temperature.
  • a suitable reducing agent such as e.g. sodium borohydride
  • a suitable solvent such as e.g. methanol or ethanol at temperatures between 0°C and room temperature.
  • R 2' and R 2''' denote hydrogen the compounds of formula LXIX can be transformed into compounds of formula LXX by oxidation. This oxidation can be carried out with Dess-Martin-Periodinan ( J. Chem. Soc.
  • this transformation can be performed by reaction with RuCl 3 or tetrapropylammonium perrhutenate in the presence of N-methylmorpholin-N-oxyde in acetonitrile or dichlormethane, or by an oxidation catalysed by 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) in the presence of iodine and a base as for example sodium bicarbonate in a solvent such as e.g.
  • TEMPO 2,2,6,6-tetramethyl-piperidin-1-oxyl
  • dichloromethane tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between -30°C and 80°C but preferably between 0°C and 40°C.
  • An alkylation reaction of compounds of formula LXX with a suitable alkyl metal compound such as e.g. alkylmagnesium halogenide-, or alkyllithium-reagent, in a suitable solvent such as e.g.
  • this transformation can be performed by reaction with RuCl 3 or tetrapropylammonium perrhutenate in the presence of N-methylmorpholin-N-oxyde in acetonitrile or dichlormethane, or by an oxidation catalysed by 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) in the presence of iodine and a base as for example sodium bicarbonate in a solvent such as e.g.
  • TEMPO 2,2,6,6-tetramethyl-piperidin-1-oxyl
  • dichloromethane tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between -30°C and 80°C but preferably between 0°C and 40°C.
  • a suitable alkyl metal compound such as e.g. alkylmagnesium halogenide-, or alkyllithium-reagent
  • a suitable solvent such as e.g.N,N-dimethylformamide, acetonitrile, dimethylsulfoxide, 1,4-dioxane or tetrahydrofurane and subsequent alkylation with a suitable alkylating reagent such as e.g.
  • Carbonyl compounds of formula LXX can also be formed by reacting compounds of formula LXVII with ozone in a suitable solvent such as e.g.
  • compounds of formula LXV can be converted into compounds of formula LXXI, wherein R c denotes a methyl- or ethyl- substituent, via carbonylation at a suitable pressure of carbon monoxide such as e.g. 20 bar in a suitable solvent such as e.g. methanol, ethanol or mixtures of methanol or ethanol with with N,N-dimethylformamide in the presence of a suitable catalyst such as e.g.
  • aromatic hydroxy groups can be converted into aromatic sulfonyloxy groups such as methylsulfonyloxy, tosylsulfonyloxy or trifluoromethylsulfonyloxy.
  • This transformation is performed by reacting compounds with aromatic hydroxy group with a sulfonyl anhydride, sulfonylchloride or sulfonylimide in a solvent such as e.g.
  • dichloromethane 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane, acetonitrile or toluene at temperatures between -78°C and 40°C, in the presence of a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine or 2,6-lutidine, optionally in the presence of an acylation catalyst as 4-dimethylamino-pyridine (DMAP).
  • a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine or 2,6-lutidine
  • an acylation catalyst as 4-dimethylamino-pyridine (DMAP).
  • aromatic sulfonyloxy groups can be further transformed into alkenyl groups or optionally substituted cyclopropyl groups by reacting the compounds with aromatic sulfonyloxy groups with potassium alkenyltrifluoroborates, alkenyl-boronic acids, alkenyl-boronic acid pinacol esters, optionally substituted cyclopropyl-boronic acids or optionally substituted cyclopropyl-boronic acid pinacol esters in toluene, N,N-dimethylformamide, isopropanol, acetonitrile, 1,4-dioxane or tetrahydrofurane or mixtures of toluene and tetrahydrofurane in the presence of a base as such as e.g.
  • aqueous sodium carbonate aqueous potassium carbonate, aqueous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine and in the presence of a catalyst such as e.g.
  • a palladium source such as e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(O) and a suitable ligand like e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl at temperatures between 0°C and 180°C, but preferably between room temperature and 120°C.
  • Alkenyl groups can be transformed into an optionally substituted cyclopropyl group by a Simmons-Smith reaction. This reaction is performed by reacting with bromo-iodo-methane or diiodomethane and diethylzinc, optionally in the presence of trifluoroacetic acid, in a solvent such as e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene at temperatures between -50°C and 80°C, but preferably between -10°C and room temperature.
  • Alkoxycarbonyl groups can be transformed into dialkylmethanol groups.
  • This transformation is performed by reacting with an alkyllithium reagent or with an alkyl-Grignard reagent in a solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene at temperatures between -50°C and 80°C, but preferably between -20°C and room temperature.
  • a solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • alkoxycarbonyl groups can be transformed into compounds hydroxymethyl groups.
  • This transformation is performed by reacting with a reducing reagent such as e.g.
  • Hydroxy groups can be further transformed into alkoxy groups by alkylation. This transformation is performed by reacting with an alkylating agent such as e.g. an alkyl halogenide, methanesulfonic acid-alkyl-ester, p-toluenesulfonic acid-alkyl-ester or trifluoromethanesulfonic acid-alkyl-ester in the presence of a base such as e.g.
  • an alkylating agent such as e.g. an alkyl halogenide, methanesulfonic acid-alkyl-ester, p-toluenesulfonic acid-alkyl-ester or trifluoromethanesulfonic acid-alkyl-ester in the presence of a base such as e.g.
  • a solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane, N,N-dimethylformamide, acetonitrile or toluene at temperatures between -50°C and 80°C, but preferably between - 20°C and 50°C.
  • any reactive groups present such as carboxy-, carbonyl-, hydroxy-, amino-, alkylamino- or imino-groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a protecting group for a carboxy group may be the methyl-, ethyl-,-tert.-butyl- or benzyl-group.
  • a protecting group for a carbonyl group may be an acetal or ketal like the 1,3-dioxolane- or the 1,3-dioxane-group.
  • a protecting group for a hydroxy group may be a trimethylsilyl-, tert.-butyldimethylsilyl-, acetyl-, trityl-, benzyl- or tetrahydropyranyl-group.
  • Protecting groups for an amino, alkylamino or imino group may be, for example, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
  • the cleavage of a carboxymethyl- or a carboxyethyl-group can for example be carried out hydrolytically in an aqueous solvent, e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or 1,4-dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali base as for example lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically in the presence of e.g. iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.
  • an aqueous solvent e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or 1,
  • An acetal or ketal can be cleaved with acetic acid, trifluoroacetic acid, hydrochloric acid, sulphuric acid or pyridiumium-p-toluene sulfonate in mixtures with water or in organic solvents like for example dichloromethane, 1,2-dichloroethane, tetrahydrofurane, 1,4-dioxane, toluene or acetone at temperatures between -20°C and 150°C, but preferably between 0°C and 120°C.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetatetetrahydrofurane, 1,4-dioxane or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or with the addition of a base such as triethylamine at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as dichloromethane, 1,4-dioxane, methanol or diethylether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as dichloromethane, 1,4-dioxane, methanol or diethylether.
  • a trimethylsilyl- or tert.-butyldimethylsilyl-group is cleaved with a fluoride reagent like for example tetrabutylammonium fluoride or caesium fluoride or with an acid like for example trifluoroacetic acid, hydrochloric acid or sulphuric acid in a solvent like e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane, acetonitrile or toluene at temperatures between -50°C and 120°C, but preferably between -20°C and 80°C.
  • a fluoride reagent like for example tetrabutylammonium fluoride or caesium fluoride or with an acid like for example trifluoroacetic acid, hydrochloric acid or sulphuric acid in a solvent like e.g. dichloromethan
  • the present invention also relates to intermediates (including their salts, stereoisomers and salts of these stereoisomers), methods and processes which are disclosed herein and which are useful in synthesizing final compounds according to this invention.
  • the present invention also relates to processes disclosed herein for preparing compounds according to this invention, which processes may be performed as described herein. Said processes may comprise one or more steps of converting and/or reacting the mentioned intermediates with the appropriate reaction partners, suitably under conditions as disclosed herein.
  • the compounds of general formula I or intermediates in the synthesis of compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.
  • cis / trans mixtures may be resolved into their cis and trans isomers, and racemic compounds may be separated into their enantiomers.
  • the cis / trans mixtures may be resolved by chromatography into the cis and trans isomers thereof.
  • the compounds of general formula I or intermediates in the synthesis of compounds of general formula I, which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I or intermediates in the synthesis of compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound.
  • Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds.
  • Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g.
  • Optically active acids in common use for such a purpose are e.g. the D- and L-forms of tartaric acid, dibenzoyltartaric acid, ditoloyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid.
  • Optically active alcohols applicable as auxiliary residues may be, for example, (+) or (-)-menthol and optically active acyl groups in amides may be, for example, (+)- or (-)-menthyloxycarbonyl.
  • the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the pharmaceutically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Corresponding processes are known for the skilled person.
  • the compounds of formula I may be obtained - depending on their individual chemical nature and the individual nature of the acid or base used - as free compound or containing said acid or base in an stoechiometric or non-stoechiometric quantity (e.g. as a salt).
  • the acid / base contained can be analyzed according to art-known procedures, e.g. by titration or NMR, and, optionally, removed according to procedures familiar to the skilled person.
  • salts of the compounds of the formula I may be converted into the free compounds.
  • Corresponding processes are known to the skilled person, e.g. via neutralization.
  • Salts can be obtained by combining or reacting the free compounds with the desired acids or bases, e.g. by dissolving or suspending the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or 1,4-dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, a low-molecular-weight aliphatic alcohol, such as methanol, ethanol or isopropanol, or an ester, such as ethyl acetate, or water, or a mixture thereof) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent e.g. a ketone, such as acetone, methyl ethyl ketone or methyl is
  • the salts can be obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted to another, e.g. by reaction with an appropriate acid or base or by means of a suitable ion exchanger. Likewise, salts obtained can be converted into the free compounds, which can in turn be converted into salts, by alkalization or by acidification. In this manner, pharmaceutically unacceptable salts can be converted into pharmaceutically acceptable salts.
  • the substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
  • the hereinafter described compounds have been characterized through their characteristic mass after ionisation in a mass-spectrometer, their R f -Value on thin-layer-chromatography plate and/or their retention time on an analytical HPLC.
  • Method 1 Column: Agilent Zorbax Bonus RP, 50 x 2.1 mm, 3.5 ⁇ m; 1.2 ml/min; UV-Detection: DAD 190-400 nm nm; Eluent A: Water (0.1 % Formic acid), Eluent B: Acetonitrile (0.1 % Formic acid) Gradient: Time (min.) % Eluent B 0.00 10 4.50 99 5.00 99 5.50 10
  • Method 2 Column: Agilent Zorbax Bonus RP, 50 x 2.1 mm, 3.5 ⁇ m; 1.2 ml/min; UV-Detection: DAD 190-400 nm nm; Eluent A: Water (0.1 % Formic acid), Eluent B: Acetonitrile (0.1 % Formic acid) Gradient: Time (min.) % Eluent B 0.00 10 1.00 75 1.30 75 2.30 99 4.40 99 5.00 10
  • Method 3 Column: Sunfire C18, 30 x 4.6
  • Method 21 Column: Varian Microsorb 100 C18, 30 x 4.6 mm, UV-Detection: 210-380 nm; Eluent A: Water (0.13 % Trifluoacetic acid), Eluent B: Acetonitrile Gradient: Time (min.) % Eluent B Flow ml/min.
  • Method 22 Column: Varian Microsorb 100 C18, 30 x 4.6 mm, UV-Detection: 210-380 nm; Eluent A: Water (0.13 % Trifluoacetic acid), Eluent B: Methanol Gradient: Time (min.) % Eluent B Flow ml/min.
  • 1,1 ml 4-iodobenzotrifluoride are dissolved in 60 ml tetrahydrofurane and cooled to -20°C.
  • 3,7 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane are added dropwise and the solution is stirred for further 5 hours.
  • the solution is cooled to -40°C and 1,17 g (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 5 ml tetrahydrofurane are added dropwise.
  • the Grignard reagent is added dropwise via syringe to a solution of 880 mg (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 10 ml tetrahydrofurane at -50°C.
  • the reaction is stirred for 1 hour at -50°C and then quenched by dropwise addition of 10 ml methanol.
  • the mixture is partitioned between dichloromethane and saturated ammonium chloride. The organic phase is washed with brine and dried with sodium sulphate.
  • the precipitate is collected by filtration and washed with water and diisopropylether and dried in vacuo to give 10,6 g product.
  • the methanol of the mother liquor is evaporated in vacuo, 50 ml 1,4-dioxane are added and the mixture is refluxed for 1 hour.
  • the 1,4-dioxane is evaporated in vacuo and the precipitate is collected by filtration, washed with water and diisopropylether and dried in vacuo to give 3,2 g product.
  • 2,2 g 4-lodoacetophenone are dissolved in 4,5 ml tetrahydrodurane and 20 ml methanol, treated with 3,0 g [bis(2-methoxyethyl)amino]sulfur-trifluoride (BAST) dissolved in 3 ml tetrahydrofurane and stirred for 4 days at 50°C.
  • BAST bis(2-methoxyethyl)amino]sulfur-trifluoride
  • the mixture is then partitioned between dichloromethane and saturated aqueous sodium bicarbonate.
  • the aqueous phase is extracted three times with dichloromethane and the combined organic phases are dried with sodium sulphate.
  • 1,3 g (S)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol are dissolved in 20 ml dichloromethane, cooled to 0°C and mixed with 1,13 g 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1 H)-on (Dess-Martin-Periodinan). The mixture is stirred for 12 hours while warming to room temperature.
  • 1,7 g sodium hydride (60% in mineral oil) are suspended in 10 ml dimethylsulfoxide at 0°C.
  • the a solution of 6,4 ml diethyl 2-methylmalonate in 10 ml dimethylsulfoxide is added dropwise.
  • the mixture is stirred for 30 minutes and then diluted with 20 ml dimethylsulfoxide.
  • a solution of 5 g 4-fluornitrobenzene is added dropwise.
  • the mixture is stirred for 12 hours while warming to room temperature. Then it is partitioned between icewater and ethylacetate.
  • the aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed with brine.
  • the mixture is partitioned between saturated solution of sodium bicarbonate in water and dichloromethane.
  • the aqueous phase is twice extracted with dichloromethane.
  • the combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo.
  • the residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 90:10).
  • 1,28 g (3R,9S)-methyl 9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4'-pyran]-4-carboxylate are dissolved in 10 ml tetrahydrofurane cooled to -10°C and treated dropwise with 1,2 ml of a 1 M solution of lithiumaluminium hydride in tetrahydrofurane. The mixture is warmed to room temperature and stirred for 1 hour.
  • active substance denotes one or more compounds according to the invention, including the salts thereof.
  • active substance also includes the additional active substances.
  • 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg
  • the active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
  • 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
  • the active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm.
  • the granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
  • 1 capsule contains: active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg
  • the active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • Capsule shell size 1 hard gelatine capsule.
  • 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg
  • the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP20110704227 2010-02-19 2011-02-17 Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation Active EP2536733B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP20110704227 EP2536733B1 (en) 2010-02-19 2011-02-17 Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10154086 2010-02-19
EP20110704227 EP2536733B1 (en) 2010-02-19 2011-02-17 Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
PCT/EP2011/052376 WO2011101424A1 (en) 2010-02-19 2011-02-17 Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation

Publications (2)

Publication Number Publication Date
EP2536733A1 EP2536733A1 (en) 2012-12-26
EP2536733B1 true EP2536733B1 (en) 2014-11-26

Family

ID=43877277

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20110704227 Active EP2536733B1 (en) 2010-02-19 2011-02-17 Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation

Country Status (22)

Country Link
US (2) US9029544B2 (es)
EP (1) EP2536733B1 (es)
JP (1) JP5780528B2 (es)
KR (1) KR20130000379A (es)
CN (1) CN102869667A (es)
AP (1) AP2012006390A0 (es)
AR (1) AR080228A1 (es)
AU (1) AU2011217206A1 (es)
BR (1) BR112012020591A2 (es)
CA (1) CA2790643A1 (es)
CL (1) CL2012002035A1 (es)
CO (1) CO6592112A2 (es)
EA (1) EA201201160A1 (es)
EC (1) ECSP12012157A (es)
MA (1) MA34007B1 (es)
MX (1) MX2012009149A (es)
PE (1) PE20121743A1 (es)
SG (1) SG183321A1 (es)
TN (1) TN2012000418A1 (es)
TW (1) TW201139445A (es)
UY (1) UY33229A (es)
WO (1) WO2011101424A1 (es)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2010009607A (es) 2008-03-05 2010-09-30 Boehringer Ingelheim Int Derivados de piridina triciclicos, medicamentos que contienen tales compuestos, su uso y proceso para su preparacion.
AP2012006390A0 (en) 2010-02-19 2012-08-31 Boehringer Ingelheim Int Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
EP2675811A1 (en) * 2011-02-17 2013-12-25 Boehringer Ingelheim International GmbH Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
AR087577A1 (es) * 2011-08-17 2014-04-03 Boehringer Ingelheim Int Derivados de furo[3,4-c]quinolina, medicamentos que contienen dichos compuestos, su uso y proceso para su preparacion
WO2013024149A1 (en) * 2011-08-18 2013-02-21 Boehringer Ingelheim International Gmbh Crystalline forms of octahydro-3h-spiro [furo [3, 4-c] quinoline -1, 4 '-pyran] -9-ol
US8633182B2 (en) 2012-05-30 2014-01-21 Boehringer Ingelheim International Gmbh Indanyloxyphenylcyclopropanecarboxylic acids
CN103882766B (zh) * 2014-03-21 2015-10-28 湖南中烟工业有限责任公司 一种除去包装卡纸中酮类物质的除酮添加剂及其应用
CN103866646B (zh) * 2014-03-21 2015-10-28 湖南中烟工业有限责任公司 一种生产无酮转移卡纸的工艺

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4798619A (en) 1980-06-02 1989-01-17 American Cyanamid Co. 2-(2-imidazolin-2-yl)-pyridines and quinolines and use of said compounds as herbicidal agents
US4475407A (en) 1982-12-27 1984-10-09 Brunswick Corporation Temperature compensated flow sensor
CH664578A5 (de) * 1985-01-15 1988-03-15 Ciba Geigy Ag Ringsubstituierte 4-azaphthalide.
EP0429464B1 (en) 1988-08-16 1994-11-23 The Upjohn Company Bivalent ligands effective for blocking acat enzyme
KR100464895B1 (ko) 1995-09-29 2005-05-16 글락소 웰컴 에스피에이 Nmda길항제로서의테트라히드로퀴놀린
DE19627431A1 (de) 1996-07-08 1998-01-15 Bayer Ag Heterocyclisch kondensierte Pyridine
HRP970330B1 (en) * 1996-07-08 2004-06-30 Bayer Ag Cycloalkano pyridines
JP2894445B2 (ja) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
EP1009741A1 (de) 1997-09-04 2000-06-21 Basf Aktiengesellschaft Neue carbonsäurederivate, ihre herstellung und verwendung als gemischte et a?/et b?-endothelin-rezeptorantagonisten
DE19741051A1 (de) 1997-09-18 1999-03-25 Bayer Ag Hetero-Tetrahydrochinoline
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
ES2244216T3 (es) 1998-09-25 2005-12-01 Monsanto Company Amino-(n+1)-alcanoles 1-sustituidos halogenados (r)-quirales utiles para inhibir la actividad de la proteina de transferencia del ester de colesterillo.
US20010018446A1 (en) 1999-09-23 2001-08-30 G.D. Searle & Co. Substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
US6479552B2 (en) 1999-09-23 2002-11-12 G.D. Searle & Co. Use of substituted N, N-disubstituted diamino compounds for inhibiting cholesteryl ester transfer protein activity
US6521607B1 (en) 1999-09-23 2003-02-18 Pharmacia Corporation (R)-chiral halogenated substituted N-phenoxy N-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
DE10148436A1 (de) 2001-10-01 2003-04-17 Bayer Ag Tetrahydrochinoline
DE10238243A1 (de) * 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
AU2005233160B2 (en) 2004-04-13 2011-06-02 Merck Sharp & Dohme Corp. CETP inhibitors
PE20060653A1 (es) 2004-08-31 2006-09-27 Glaxo Group Ltd Derivados triciclicos condensados como moduladores del receptor 5-ht1
PT1828137E (pt) 2004-12-18 2012-07-04 Bayer Pharma AG Derivados de tetra-hidroquinolina substituídos com 4- cicloalquilo e sua utilização enquanto medicamentos
DE102004060997A1 (de) * 2004-12-18 2006-06-22 Bayer Healthcare Ag Chemische Verbindung und ihre Verwendung
MX2007007187A (es) 2004-12-18 2007-08-14 Bayer Healthcare Ag Derivados de (5s)-3-[(s)-fluoro-(4-trifluorometilfenil)metil]-5,6, 7,8-tetrahidroquinolin-5-ol y su uso como inhibidores de la proteina de transferencia de ester de colesterol.
JP2008201760A (ja) 2007-02-22 2008-09-04 Tokyo Univ Of Agriculture & Technology 光学活性スピロ化合物及びその製造方法
MX2010009607A (es) 2008-03-05 2010-09-30 Boehringer Ingelheim Int Derivados de piridina triciclicos, medicamentos que contienen tales compuestos, su uso y proceso para su preparacion.
TWI396689B (zh) 2008-11-14 2013-05-21 Amgen Inc 作為磷酸二酯酶１０抑制劑之吡衍生物
AP2012006390A0 (en) 2010-02-19 2012-08-31 Boehringer Ingelheim Int Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
EP2675811A1 (en) * 2011-02-17 2013-12-25 Boehringer Ingelheim International GmbH Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
AR087577A1 (es) 2011-08-17 2014-04-03 Boehringer Ingelheim Int Derivados de furo[3,4-c]quinolina, medicamentos que contienen dichos compuestos, su uso y proceso para su preparacion
WO2013024149A1 (en) 2011-08-18 2013-02-21 Boehringer Ingelheim International Gmbh Crystalline forms of octahydro-3h-spiro [furo [3, 4-c] quinoline -1, 4 '-pyran] -9-ol

Also Published As

Publication number Publication date
WO2011101424A1 (en) 2011-08-25
CL2012002035A1 (es) 2013-02-01
CO6592112A2 (es) 2013-01-02
SG183321A1 (en) 2012-09-27
US20120046304A1 (en) 2012-02-23
ECSP12012157A (es) 2012-10-30
CN102869667A (zh) 2013-01-09
EA201201160A1 (ru) 2013-04-30
CA2790643A1 (en) 2011-08-25
EP2536733A1 (en) 2012-12-26
UY33229A (es) 2011-09-30
JP2013519709A (ja) 2013-05-30
JP5780528B2 (ja) 2015-09-16
AP2012006390A0 (en) 2012-08-31
MA34007B1 (fr) 2013-02-01
PE20121743A1 (es) 2012-12-22
US20120053197A1 (en) 2012-03-01
BR112012020591A2 (pt) 2017-10-10
AR080228A1 (es) 2012-03-21
TW201139445A (en) 2011-11-16
KR20130000379A (ko) 2013-01-02
MX2012009149A (es) 2012-09-28
US9029544B2 (en) 2015-05-12
AU2011217206A1 (en) 2012-08-02
TN2012000418A1 (en) 2014-01-30

Similar Documents

Publication Publication Date Title
EP2536733B1 (en) Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
EP2268644B1 (en) Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
US20160272590A1 (en) Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
EP2760868B1 (en) Furo[3,4-c]quinoline derivatives, medicaments containing such compounds, their use and process for their preparation
US20130053404A1 (en) Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
US20240150293A1 (en) Spirocyclohexane derivatives, pharmaceutical compositions containing them and their uses as anti-apoptotic inhibitors
AU2022240454B2 (en) Selective estrogen receptor degraders
TW201326179A (zh) 呋喃［３，４－ｃ］喹啉衍生物，含該化合物之藥物，其用途及製法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120919

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

17Q First examination report despatched

Effective date: 20131002

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20140604

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 698118

Country of ref document: AT

Kind code of ref document: T

Effective date: 20141215

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602011011710

Country of ref document: DE

Effective date: 20150108

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 5

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20141126

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 698118

Country of ref document: AT

Kind code of ref document: T

Effective date: 20141126

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150326

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150326

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150226

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150227

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602011011710

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150217

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150228

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150228

26N No opposition filed

Effective date: 20150827

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150217

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20110217

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141126

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230221

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240219

Year of fee payment: 14

Ref country code: GB

Payment date: 20240219

Year of fee payment: 14